Category Archives: Dolor

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Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis.

Category : Dolor

Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis.

Pain. 2017 Sep 01;:

Authors: Philpott HT, O’Brien M, McDougall JJ

Abstract
Osteoarthritis (OA) is a multifactorial joint disease, which includes joint degeneration, intermittent inflammation, and peripheral neuropathy. Cannabidiol (CBD) is a non-euphoria producing constituent of cannabis that has the potential to relieve pain. The aim of this study was to determine if CBD is anti-nociceptive in OA, and whether inhibition of inflammation by CBD could prevent the development of OA pain and joint neuropathy. OA was induced in male Wistar rats (150-175g) by intra-articular injection of sodium monoiodoacetate (MIA; 3mg). On day 14 (end stage OA), joint afferent mechanosensitivity was assessed using in vivo electrophysiology while pain behaviour was measured by von Frey hair algesiometry and dynamic incapacitance. To investigate acute joint inflammation, blood flow and leukocyte trafficking were measured on day 1 post-MIA. Joint nerve myelination was calculated by G-ratio analysis. The therapeutic and prophylactic effects of peripheral CBD (100-300μg) were assessed. In end stage OA, CBD dose-dependently decreased joint afferent firing rate, and increased withdrawal threshold and weight bearing (p<0.0001; n=8). Acute, transient joint inflammation was reduced by local CBD treatment (p<0.0001; n=6). Prophylactic administration of CBD prevented the development of MIA-induced joint pain at later time points (p<0.0001; n=8), and was also found to be neuroprotective (p<0.05; n=6-8). The data presented here indicate that local administration of CBD blocked OA pain. Prophylactic CBD treatment prevented the later development of pain and nerve damage in these OA joints. These findings suggest that CBD may be a safe, useful therapeutic for treating OA joint neuropathic pain.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

PMID: 28885454 [PubMed – as supplied by publisher]

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A randomised controlled cross-over double-blind pilot study protocol on THC:CBD oromucosal spray efficacy as an add-on therapy for post-stroke spasticity.

Category : Dolor

A randomised controlled cross-over double-blind pilot study protocol on THC:CBD oromucosal spray efficacy as an add-on therapy for post-stroke spasticity.

BMJ Open. 2017 Sep 07;7(9):e016843

Authors: Marinelli L, Balestrino M, Mori L, Puce L, Rosa GM, Giorello L, Currà A, Fattapposta F, Serrati C, Gandolfo C, Abbruzzese G, Trompetto C

Abstract
INTRODUCTION: Stroke is the most disabling neurological disorder and often causes spasticity. Transmucosal cannabinoids (tetrahydrocannabinol and cannabidiol (THC:CBD), Sativex) is currently available to treat spasticity-associated symptoms in patients with multiple sclerosis. Cannabinoids are being considered useful also in the treatment of pain, nausea and epilepsy, but may bear and increased risk for cardiovascular events. Spasticity is often assessed with subjective and clinical rating scales, which are unable to measure the increased excitability of the monosynaptic reflex, considered the hallmark of spasticity. The neurophysiological assessment of the stretch reflex provides a precise and objective method to measure spasticity. We propose a novel study to understand if Sativex could be useful in reducing spasticity in stroke survivors and investigating tolerability and safety by accurate cardiovascular monitoring.
METHODS AND ANALYSIS: We will recruit 50 patients with spasticity following stroke to take THC:CBD in a double-blind placebo-controlled cross-over study. Spasticity will be assessed with a numeric rating scale for spasticity, the modified Ashworth scale and with the electromyographical recording of the stretch reflex. The cardiovascular risk will be assessed prior to inclusion. Blood pressure, heart rate, number of daily spasms, bladder function, sleep disruption and adverse events will be monitored throughout the study. A mixed-model analysis of variance will be used to compare the stretch reflex amplitude between the time points; semiquantitative measures will be compared using the Mann-Whitney test (THC:CBD vs placebo) and Wilcoxon test (baseline vs treatment).
ETHICS AND DISSEMINATION: The study was registered on the EudraCT database with number 2016-001034-10 and approved by both the Italian Medicines Agency (Agenzia Italiana del Farmaco) and local Ethics Committee ‘Comitato Etico Regionale della Liguria’. Data will be made anonymous and uploaded to a open access repository. Results will be disseminated by presentations at national and international conferences and by publication in journals of clinical neuroscience and neurology.

PMID: 28882919 [PubMed – in process]

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A selective review of medical cannabis in cancer pain management.

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A selective review of medical cannabis in cancer pain management.

Ann Palliat Med. 2017 Aug 23;:

Authors: Blake A, Wan BA, Malek L, DeAngelis C, Diaz P, Lao N, Chow E, O’Hearn S

Abstract
Insufficient management of cancer-associated chronic and neuropathic pain adversely affects patient quality of life. Patients who do not respond well to opioid analgesics, or have severe side effects from the use of traditional analgesics are in need of alternative therapeutic op-tions. Anecdotal evidence suggests that medical cannabis has potential to effectively manage pain in this patient population. This review presents a selection of representative clinical studies, from small pilot studies conducted in 1975, to double-blind placebo-controlled trials conducted in 2014 that evaluated the efficacy of cannabinoid-based therapies containing tetrahydrocannabinol (THC) and cannabidiol (CBD) for reducing cancer-associated pain. A review of literature published on Medline between 1975 and 2017 identified five clinical studies that evaluated the effect of THC or CBD on controlling cancer pain, which have been reviewed and summarised. Five studies that evaluated THC oil capsules, THC:CBD oromucosal spray (nabiximols), or THC oromucosal sprays found some evidence of cancer pain reduction associated with these therapies. A variety of doses ranging from 2.7-43.2 mg/day THC and 0-40 mg/day CBD were administered. Higher doses of THC were correlated with increased pain relief in some studies. One study found that significant pain relief was achieved in doses as low as 2.7-10.8 mg THC in combination with 2.5-10.0 mg CBD, but there was conflicting evidence on whether higher doses provide superior pain relief. Some reported side effects include drowsiness, hypotension, mental clouding, and nausea and vomiting. There is evidence suggesting that medical cannabis reduces chronic or neu-ropathic pain in advanced cancer patients. However, the results of many studies lacked statistical power, in some cases due to limited number of study subjects. Therefore, there is a need for the conduct of further double-blind, placebo-controlled clinical trials with large sample sizes in order to establish the optimal dosage and efficacy of different cannabis-based therapies.

PMID: 28866904 [PubMed – as supplied by publisher]

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Cannabis and Pain: A Clinical Review.

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Cannabis and Pain: A Clinical Review.

Cannabis Cannabinoid Res. 2017;2(1):96-104

Authors: Hill KP, Palastro MD, Johnson B, Ditre JW

Abstract
Introduction: Cannabis has been used for medical purposes across the world for centuries. As states and countries implement medical and recreational cannabis policies, increasing numbers of people are using cannabis pharmacotherapy for pain. There is a theoretical rationale for cannabis’ efficacy for pain management, although the subjective pain relief from cannabis may not match objective measurements of analgesia. As more patients turn to cannabis for pain relief, there is a need for additional scientific evidence to evaluate this increase. Materials and Methods: Research for this review was performed in the PubMed/National Library of Medicine database. Discussion: Preclinical studies demonstrate a narrow therapeutic window for cannabis as pharmacotherapy for pain; the body of clinical evidence for this indication is not as extensive. A recent meta-analysis of clinical trials of cannabis and cannabinoids for pain found modest evidence supporting the use of cannabinoid pharmacotherapy for pain. Recent epidemiological studies have provided initial evidence for a possible reduction in opioid pharmacotherapy for pain as a result of increased implementation of medical cannabis regimens. Conclusion: With increased use of medical cannabis as pharmacotherapy for pain comes a need for comprehensive risk-benefit discussions that take into account cannabis’ significant possible side effects. As cannabis use increases in the context of medical and recreational cannabis policies, additional research to support or refute the current evidence base is essential to attempt to answer the questions that so many healthcare professionals and patients are asking.

PMID: 28861509 [PubMed]

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Training and Practices of Cannabis Dispensary Staff.

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Training and Practices of Cannabis Dispensary Staff.

Cannabis Cannabinoid Res. 2016;1(1):244-251

Authors: Haug NA, Kieschnick D, Sottile JE, Babson KA, Vandrey R, Bonn-Miller MO

Abstract
Introduction: The proliferation of cannabis dispensaries within the United States has emerged from patient demand for the legalization of cannabis as an alternative treatment for a number of conditions and symptoms. Unfortunately, nothing is known about the practices of dispensary staff with respect to recommendation of cannabis strains/concentrations for specific patient ailments. To address this limitation, the present study assessed the training and practices of cannabis dispensary staff. Materials and Methods: Medical and nonmedical dispensary staff (n=55) were recruited via e-mail and social media to complete an online survey assessing their demographic characteristics, dispensary features, patient characteristics, formal training, and cannabis recommendation practices. Results: Fifty-five percent of dispensary staff reported some formal training for their position, with 20% reporting medical/scientific training. A majority (94%) indicated that they provide specific cannabis advice to patients. In terms of strains, dispensary staff trended toward recommendations of Indica for anxiety, chronic pain, insomnia, nightmares, and Tourette’s syndrome. They were more likely to recommend Indica and hybrid plants for post-traumatic stress disorder (PTSD)/trauma and muscle spasms. In contrast, staff were less likely to recommend Indica for depression; hybrid strains were most often recommended for amyotrophic lateral sclerosis (ALS). In terms of cannabinoid concentrations, dispensary staff were most likely to recommend a 1:1 ratio of delta-9-tetrahydrocannabinol (THC):cannabidiol (CBD) for patients suffering from anxiety, Crohn’s disease, hepatitis C, and PTSD/trauma, while patients seeking appetite stimulation were most likely to be recommended THC. Staff recommended high CBD for arthritis and Alzheimer’s disease and a high CBD or 1:1 ratio for ALS, epilepsy, and muscle spasms. Conclusions: Although many dispensary staff are making recommendations consistent with current evidence, some are recommending cannabis that has either not been shown effective for, or could exacerbate, a patient’s condition. Findings underscore the importance of consistent, evidence-based, training of dispensary staff who provide specific recommendations for patient medical conditions.

PMID: 28861496 [PubMed]

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Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads.

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Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads.

Adv Pharmacol. 2017;80:67-134

Authors: Russo EB, Marcu J

Abstract
The golden age of cannabis pharmacology began in the 1960s as Raphael Mechoulam and his colleagues in Israel isolated and synthesized cannabidiol, tetrahydrocannabinol, and other phytocannabinoids. Initially, THC garnered most research interest with sporadic attention to cannabidiol, which has only rekindled in the last 15 years through a demonstration of its remarkably versatile pharmacology and synergy with THC. Gradually a cognizance of the potential of other phytocannabinoids has developed. Contemporaneous assessment of cannabis pharmacology must be even far more inclusive. Medical and recreational consumers alike have long believed in unique attributes of certain cannabis chemovars despite their similarity in cannabinoid profiles. This has focused additional research on the pharmacological contributions of mono- and sesquiterpenoids to the effects of cannabis flower preparations. Investigation reveals these aromatic compounds to contribute modulatory and therapeutic roles in the cannabis entourage far beyond expectations considering their modest concentrations in the plant. Synergistic relationships of the terpenoids to cannabinoids will be highlighted and include many complementary roles to boost therapeutic efficacy in treatment of pain, psychiatric disorders, cancer, and numerous other areas. Additional parts of the cannabis plant provide a wide and distinct variety of other compounds of pharmacological interest, including the triterpenoid friedelin from the roots, canniprene from the fan leaves, cannabisin from seed coats, and cannflavin A from seed sprouts. This chapter will explore the unique attributes of these agents and demonstrate how cannabis may yet fulfil its potential as Mechoulam’s professed “pharmacological treasure trove.”

PMID: 28826544 [PubMed – in process]

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Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies.

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Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies.

Br J Pain. 2017 Aug;11(3):119-133

Authors: Fallon MT, Albert Lux E, McQuade R, Rossetti S, Sanchez R, Sun W, Wright S, Lichtman AH, Kornyeyeva E

Abstract
BACKGROUND: Opioids are critical for managing cancer pain, but may provide inadequate relief and/or unacceptable side effects in some cases.
OBJECTIVE: To assess the analgesic efficacy of adjunctive Sativex (Δ(9)-tetrahydrocannabinol (27 mg/mL): cannabidiol (25 mg/mL)) in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy.
METHODS: This report describes two phase 3, double-blind, randomized, placebo-controlled trials. Eligible patients had advanced cancer and average pain numerical rating scale (NRS) scores ≥4 and ≤8 at baseline, despite optimized opioid therapy. In Study-1, patients were randomized to Sativex or placebo, and then self-titrated study medications over a 2-week period per effect and tolerability, followed by a 3-week treatment period. In Study-2, all patients self-titrated Sativex over a 2-week period. Patients with a ≥15% improvement from baseline in pain score were then randomized 1:1 to Sativex or placebo, followed by 5-week treatment period (randomized withdrawal design).
RESULTS: The primary efficacy endpoint (percent improvement (Study-1) and mean change (Study-2) in average daily pain NRS scores) was not met in either study. Post hoc analyses of the primary endpoints identified statistically favourable treatment effect for Sativex in US patients <65 years (median treatment difference: 8.8; 95% confidence interval (CI): 0.00-17.95; p = 0.040) that was not observed in patients <65 years from the rest of the world (median treatment difference: 0.2; 95% CI: -5.00 to 7.74; p = 0.794). Treatment effect in favour of Sativex was observed on quality-of-life questionnaires, despite the fact that similar effects were not observed on NRS score. The safety profile of Sativex was consistent with earlier studies, and no evidence of abuse or misuse was identified.
CONCLUSIONS: Sativex did not demonstrate superiority to placebo in reducing self-reported pain NRS scores in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy, although further exploration of differences between United States and patients from the rest of the world is warranted.

PMID: 28785408 [PubMed]

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Sleep disturbances and severe stress as glial activators: key targets for treating central sensitization in chronic pain patients?

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Sleep disturbances and severe stress as glial activators: key targets for treating central sensitization in chronic pain patients?

Expert Opin Ther Targets. 2017 Jul 07;:

Authors: Nijs J, Loggia ML, Polli A, Moens M, Huysmans E, Goudman L, Meeus M, Vanderweeën L, Ickmans K, Clauw D

Abstract
INTRODUCTION: The mechanism of sensitization of the central nervous system partly explains the chronic pain experience in many patients, but the etiological mechanisms of this central nervous system dysfunction are poorly understood. Recently, an increasing number of studies suggest that aberrant glial activation takes part in the establishment and/or maintenance of central sensitization. Areas covered: This review focused on preclinical work and mostly on the neurobiochemistry studied in animals, with limited human studies available. Glial overactivation results in a low-grade neuroinflammatory state, characterized by high levels of BDNF, IL-1β, TNF-α, which in turn increases the excitability of the central nervous system neurons through mechanisms like long-term potentiation and increased synaptic efficiency. Aberrant glial activity in chronic pain might have been triggered by severe stress exposure, and/or sleeping disturbances, each of which are established initiating factors for chronic pain development. Expert opinion: Potential treatment avenues include several pharmacological options for diminishing glial activity, as well as conservative interventions like sleep management, stress management and exercise therapy. Pharmacological options include propentofylline, minocycline, β -adrenergic receptor antagonists, and cannabidiol. Before translating these findings from basic science to clinical settings, more human studies exploring the outlined mechanisms in chronic pain patients are needed.

PMID: 28685641 [PubMed – as supplied by publisher]

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Cannabidiol Is a Potential Therapeutic for the Affective-Motivational Dimension of Incision Pain in Rats.

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Cannabidiol Is a Potential Therapeutic for the Affective-Motivational Dimension of Incision Pain in Rats.

Front Pharmacol. 2017;8:391

Authors: Genaro K, Fabris D, Arantes ALF, Zuardi AW, Crippa JAS, Prado WA

Abstract
Background: Pain involves different brain regions and is critically determined by emotional processing. Among other areas, the rostral anterior cingulate cortex (rACC) is implicated in the processing of affective pain. Drugs that interfere with the endocannabinoid system are alternatives for the management of clinical pain. Cannabidiol (CBD), a phytocannabinoid found in Cannabis sativa, has been utilized in preclinical and clinical studies for the treatment of pain. Herein, we evaluate the effects of CBD, injected either systemically or locally into the rACC, on mechanical allodynia in a postoperative pain model and on the negative reinforcement produced by relief of spontaneous incision pain. Additionally, we explored whether CBD underlies the reward of pain relief after systemic or rACC injection. Methods and Results: Male Wistar rats were submitted to a model of incision pain. All rats had mechanical allodynia, which was less intense after intraperitoneal CBD (3 and 10 mg/kg). Conditioned place preference (CPP) paradigm was used to assess negative reinforcement. Intraperitoneal CBD (1 and 3 mg/kg) inverted the CPP produced by peripheral nerve block even at doses that do not change mechanical allodynia. CBD (10 to 40 nmol/0.25 μL) injected into the rACC reduced mechanical allodynia in a dose-dependent manner. CBD (5 nmol/0.25 μL) did not change mechanical allodynia, but reduced peripheral nerve block-induced CPP, and the higher doses inverted the CPP. Additionally, CBD injected systemically or into the rACC at doses that did not change the incision pain evoked by mechanical stimulation significantly produced CPP by itself. Therefore, a non-rewarding dose of CBD in sham-incised rats becomes rewarding in incised rats, presumably because of pain relief or reduction of pain aversiveness. Conclusion: The study provides evidence that CBD influences different dimensions of the response of rats to a surgical incision, and the results establish the rACC as a brain area from which CBD evokes antinociceptive effects in a manner similar to the systemic administration of CBD. In addition, the study gives further support to the notion that the sensorial and affective dimensions of pain may be differentially modulated by CBD.

PMID: 28680401 [PubMed – in process]

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Single and combined effects of delta(9) -tetrahydrocannabinol and cannabidiol in a mouse model of chemotherapy-induced neuropathic pain.

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Single and combined effects of delta(9) -tetrahydrocannabinol and cannabidiol in a mouse model of chemotherapy-induced neuropathic pain.

Br J Pharmacol. 2017 May 26;:

Authors: King KM, Myers AM, Soroka-Monzo AJ, Tuma RF, Tallarida RJ, Walker EA, Ward SJ

Abstract
BACKGROUND AND PURPOSE: It has been suggested that the non-psychoactive phytocannabinoid cannabidiol (CBD) can impact the pharmacological effects of delta-9-tetrahydrocannabinol (THC). We tested the hypothesis that CBD and THC would significantly mitigate mechanical sensitivity in a mouse model of paclitaxel-induced neuropathic pain, and that CBD+THC combinations would produce synergistic effects. We also tested the hypothesis that CBD would attenuate oxaliplatin- and vincristine- induced mechanical sensitivity.
EXPERIMENTAL APPROACH: Paclitaxel-treated mice (8.0 mg/kg IP, days 1, 3, 5 and 7) were pretreated with CBD (0.625 – 20.0 mg/kg IP), THC (0.625 – 20.0 mg/kg IP) or CBD+THC (0.04+0.04 – 20.0+20.0 mg/kg IP) and mechanical sensitivity was assessed on days 9, 14, and 21. Oxaliplatin-treated (6.0 mg/kg IP, day 1) or vincristine-treated mice (0.1 mg/kg IP days 1-7) were pretreated with CBD (1.25 – 10.0 mg/kg IP), THC (10.0 mg/kg IP), or THC+CBD (0.16 mg/kg THC + 0.16 mg/kg CBD IP).
KEY RESULTS: Both CBD and THC alone attenuated mechanical allodynia in mice treated with paclitaxel. Very low ineffective doses of CBD and THC were synergistic when given in combination. CBD also attenuated oxaliplatin- but not vincristine-induced mechanical sensitivity, while THC significantly attenuated vincristine- but not oxaliplatin-induced mechanical sensitivity. The low dose combination significantly attenuated oxaliplatin- but not vincristine-induced mechanical sensitivity.
CONCLUSIONS AND IMPLICATIONS: CBD may be potent and effective at preventing the development of CIPN, and its clinical utility may be enhanced by co-administration of low doses of THC. These treatment strategies would increase the therapeutic window of Cannabis-based pharmacotherapies.

PMID: 28548225 [PubMed – as supplied by publisher]

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